Current debate on the use of population genetic data for complex disease research is driven by the laudable goals of disease prevention and harm reduction for all, especially dispossessed, formerly enslaved, or colonized populations. This article examines one of the oldest gene-based theories of complex disease causation: the thrifty genotype hypothesis (THG). This hypothesis is emblematic of the way in which genetic research into complex disease attracts a high investment of scientific resources while contributing little to our capacity to understand these diseases and perpetuating problematic conceptions of human variation. Although there are compelling reasons to regard the high prevalence of type 2 diabetes mellitus as a by-product of our biological incapacity to cope with modern affluent and sedentary lifestyles, there is at present no consistent evidence to suggest that minority populations are especially genetically susceptible. Nor is it clear why such genetic differences would be expected, given the original pan-species orientation of the TGH. The limitations inherent in current applications of the TGH demonstrate that genetic research into complex disease demands careful attention to key environmental, social, and genetic risk factors operating within and between groups, not the simplistic attribution of between-group differences to racialized genetics. A robust interdisciplinary approach to genetic epidemiological research is proposed.